Zhao, Lihua and Raval, Vishal and Briggs, Naomi E. B. and ... Zhao, Lihua and Raval, Vishal and...

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  • From Discovery to Scale-up: α-Lipoic

    Acid:Nicotinamide Co-crystals in a Continuous

    Oscillatory Baffled Crystalliser

    Lihua Zhao, † Vishal Raval,

    † Naomi E. B. Briggs,

    † Rajni M. Bhardwaj,

    ‡ Thomas McGlone,

    † Iain D. H.

    Oswald ‡ , and Alastair J. Florence


    † EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation c/o

    Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral

    Street, Glasgow, G4 0RE, U.K.

    ‡ Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral

    Street, G4 0RE, U.K.

    KEYWORDS: α-lipoic acid, co-crystals, nicotinamide, scale-up, continuous crystallisation, oscillatory

    baffled crystalliser, phase diagram

  • 2

    ABSTRACT: The crystalline nutritional supplement α-lipoic acid degrades rapidly on exposure to

    temperatures above its melting point 65 °C and to light. A small-scale experimental co-crystal screen

    has produced three novel co-crystals of α-lipoic acid that each display enhanced thermal stability and

    differences in aqueous solubilities compared to α-lipoic acid. In each case, the initial screening

    procedure produced tens of milligrams of material enabling initial identification, characterisation and

    crystal structure determination. The structure of the α-lipoic acid:nicotinamide co-crystal was

    determined by single crystal X-ray diffraction and used for subsequent phase identification. Scale-up of

    the co-crystallisation process of α-lipoic acid with nicotinamide was then investigated in a continuous

    oscillatory baffled crystalliser. Over 1 kg of solid co-crystals was produced using a continuous

    crystallisation process in a continuous oscillatory baffled crystalliser at a throughput of 350 g/hr

    yielding a purity of 99 % demonstrating this as an effective route to rapid scale-up of a novel co-crystal


    *To whom correspondence should be addressed. E-mail: alastair.florence@strath.ac.uk. Telephone:+44-

    141-548-4877. Fax: +44-141- 552-2562.

  • 3


    α-Lipoic acid (ALA; 1,2-dithiolane-3-pentanoic acid, Fig. 1) is an anti-oxidant and essential co-

    enzyme 1 used as a nutritional supplement with applications in the treatment of diabetic neuropathy

    2, 3 ,

    Alzheimer’s disease 4 , metal poisoning

    5, 6 and liver disease.

    7 The molecule is prone to polymerisation

    and photo-decomposition associated with cleavage of the disulfide bond in the 1,2-dithiolane ring 8, 9

    (Fig. 1). The crystal structure of ALA is known 10

    (CSD 11

    : THOCAR01) and various alternative

    crystalline forms with improved chemical stability have been reported including trometamol 12


    carnitine 13

    , sodium and potassium salts. 14, 15

    Improved stability of ALA has also been achieved by

    formulation of ALA with different components including polymers 16

    and β-cyclodextrin. 17

    S S



    Fig. 1 Chemical structure of -Lipoic acid (ALA)

    Co-crystals 18-21

    offer a route to engineer critical physico-chemical properties of specialty chemicals

    including pharmaceuticals 19, 22, 23

    neutraceuticals 24, 25

    , energetic materials 26, 27

    and agrochemicals. 28

    Novel co-crystal forms also offer an opportunity to secure new intellectual property as part of the

    lifecycle management of chemical entities. 29

    There are a number of examples of systems where co-

    crystals have been shown to improve the chemical stability of otherwise labile compounds. 30, 31


    crystallisation has also been used as an effective method to purify compounds during their industrial

    scale production. 32-34

    Approaches to the effective selection of co-crystal formers for specific molecules

    have been widely reported. 21, 22, 35-38

    Methods include identifying complementary hydrogen bonding

  • 4

    motifs 21, 37-39

    and comparing the relative thermodynamic stabilities of the co-crystal and the component

    solid forms. 40

    Many different techniques have been described in the literature for obtaining co-crystal forms including

    solution crystallisation 41, 42

    , slow solvent evaporation 43, 44

    , slurry conversion 45

    , neat 46, 47

    and liquid

    assisted grinding 48

    as well as growth from melts. 49

    Recently, the use of twin-screw extrusion for the

    preparation of pharmaceutical co-crystals has also been reported. 50-52

    Among these methods, slow

    evaporation and grinding are convenient and efficient ways to produce milligram or gram quantities of

    novel co-crystals and are widely used for preparation. 53

    Once new materials have been discovered and

    the evaluation of relevant physicochemical properties has informed the selection of the most promising

    forms for a particular application, it is of considerable interest to identify efficient and rapid means of

    scaling-up these novel crystalline forms to allow further testing or exploitation of the new materials at

    larger scales. Although the twin screw extruder method provides a good alternative for making co-

    crystals with scale-up potential, speed and solvent free conditions, it does have limitations. For example,

    it can only be applied to systems with pure components, cannot be used for purification purposes, and it

    is not suitable for thermally unstable chemicals such as ALA as elevated temperature is required for the

    formation of pure co-crystals. 50, 51

    Achieving scale-up of co-crystal production remains a major

    challenge and there have been a small number of studies describing approaches for scale-up from gram

    to kilogram scales (Table 1).

  • 5

    Table 1 Reported studies on co-crystallisation scale-up

    Co-crystal system Scale Method Features Ref

    Carbamazepine (CBZ)

    :nicotinamide (NIC) and

    1 L vessel Solution cooling


    Through understanding phase



    CBZ:saccharin 30 g Solution cooling


    Based on the solubility of CBZ 54

    Caffeine:Glutaric Acid 0.2 mol/kg

    caffeine in

    1 L vessel

    Solution cooling


    Using ATR-FTIR to monitor



    Caffeine:oxalic acid and

    AMG517:sorbic acid

    200 g Co-rotating twin screw

    extruder (16 mm)

    Pre-mix two solid

    components; temperature 75 ° C and 115

    ° C for two co-



    Ibuprofen:NIC 0.2 kg/hr Co-rotating twin screw

    extruder (16 mm)

    Premix two solid components,

    temperature 70-90 ° C


    API 1:benzoic acid and API

    :maleic acid

    2.0 g (API) Solution cooling


    Anti-solvent addition to

    achieve the supersaturation

    required for co-crystallisation


    SAR1:benzoic acid 10 kg Solution crystallisation Using co-crystals for



    Lamivudine intermediate

    co-crystal with (S)-(-)-


    30 kg Solution crystallisation Separation of enantiomers by

    selective formation of the co-

    crystal with (S)-(-)-BINOL


    Solution cooling crystallisation is one of the most widely used large scale manufacturing processes in

    the chemical and pharmaceutical industries providing effective purification and control of solid form

    and other particle attributes. 57

    Mass and heat transfer are key process parameters controlling

    concentration and temperature gradients that can impact on local supersaturation and consequently

    crystal form, morphology, purity and particle size distribution 57

    during cooling and anti-solvent

    crystallisation. These factors become more critical in co-crystallisation processes due to the need to

    control precisely the process path through multiple solid-liquid equilibria.

  • 6

    Continuous reaction, work-up and crystallisation are key operations in the drive towards improving

    manufacture in the chemical and pharmaceutical industries. 58-61

    Continuous processing offers many

    potential advantages over traditional batch processes including consistent product quality, lower cost,

    small foot print, better process control, more efficient use of reagents, solvents, energy and space whilst

    minimising the production of waste materials and reactor downtime for reactor maintenance and

    cleaning. Whilst there remain challenges in the operation of continuous processing equipment within the

    highly regulated pharmaceutical manufacturing environment, there are significant drives to accelerate

    more widespread adoption of these technologies. 59, 62

    The continuous oscillatory baffled crystalliser

    (COBC) has been reported to offer advantages in controlling crystallisation processes due to plug-flow

    mixing characteristics and rapid heat transfer properties. 6